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Local Peripheral Effects of Β-Caryophyllene Through CB2 Receptors in Neuropathic Pain in Mice

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Local Peripheral Effects of Β-Caryophyllene Through CB2 Receptors in Neuropathic Pain in Mice Pharmacology & Pharmacy, 2012, 3, 397-403 1 http://dx.doi.org/10.4236/pp.2012.34053 Published Online October 2012 (http://www.SciRP.org/journal/pp) Local Peripheral Effects of β-Caryophyllene through CB2 Receptors in Neuropathic Pain in Mice Hikari Kuwahata1,2, Soh Katsuyama2,3, Takaaki Komatsu2, Hitoshi Nakamura3, Maria Tiziana Corasaniti4, Giacinto Bagetta5, Shinobu Sakurada6, Tsukasa Sakurada2*, Kazuo Takahama1 1Department of Environmental and Molecular Health and Sciences, Graduated School of Pharmaceutical Sciences, Kumamoto Uni- versity, Kumamoto, Japan; 2Department of Pharmacology, Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan; 3Department of Clinical Pharmaceutics, Tohoku Pharmaceutical University, Sendai, Japan; 4Department of Pharmacobiological Sciences, Univer- sity of Magna Gracia of Catanzaro, Catanzaro, Italy; 5Department of Pharmacobiology, University Consortium for Adaptive Disor- ders and Headach (UCADH), Section of Neuropharmacology of Normal and Pathological Neuronal Plasticity, University of Calabria, Arcavacata di Rende, Italy; 6Department of Physiology and Anatomy, Tohoku Pharmaceutical University, Sendai, Japan. Email: *[email protected] Received July 13th, 2012; revised August 15th, 2012; accepted September 10th, 2012 ABSTRACT β-Caryophyllene (BCP) is known as a common constitute of the essential oils of numerous food plants and primary component in Cannabis. In this study, we investigated the effect of local intraplantar (i.pl.) injection of BCP on me- chanical hypersensitivity induced by partial sciatic nerve ligation (PSNL) in mice. Relative to sham operation controls, mice with the PSNL displayed a maximum level of hyperresponsiveness to von Frey metallic filament on post-operative day 7. PSNL-induced allodynia was seen in the ipsilateral side of nerve ligation, but not in the contralateral side. The i.pl. injection of BCP into the ipsilateral hindpaw to PSNL attenuated mechanical allodynia in a dose-dependent manner. BCP injection into the contralateral hindpaw did not produce anti-allodynic effects, suggesting a local peripheral anti-allodynic effect of BCP. Anti-allodynic effects induced by i.pl. injection of BCP were prevented by pretreatment with the cannabinoid (CB)2 receptor antagonist AM630, but not by the CB1 receptor antagonist AM251. These data suggest that i.pl. injection of BCP could produce anti-allodynia by activating peripheral CB2 receptors, but not CB1 re- ceptors in a mouse model of neuropathic pain. Taken together, these results suggest that peripheral CB2 receptors may contribute to the effectiveness of BCP in the treatment of neuropathic pain disorders. Keywords: β-Caryophyllene (BCP); Neuropathic Pain; Partial Sciatic Nerve Ligation (PSNL); Peripheral Cannabinoid (CB) Receptor 1. Introduction staglandin E1-induced edema in rats as well as anti-ar- thritic activity [8-10]. Oral administration of BCP sig- Plants are used for various purposes including their cos- nificantly reduced the inflammation of colon [11], the metic, nutritive, and biomedical properties. Plant essen- carrageenan-induced inflammatory response in wild-type tial oils are typically composed of volatile aromatic ter- mice but not in mice lacking cannabinoid (CB) receptors penes and phenylpropanoids. The natural sesquiterpene 2 [12]. However, the antinociceptive efficacy of intraplan- β-caryophyllene (BCP) is found in many essential oils of tar (i.pl.) BCP on partial sciatic nerve ligation (PSNL)- different spice and food plants, such as clove, oregano, induced mechanical allodynia in mice is unknown. Can- thyme, black pepper and cinnamon [1,2], all of which nabinoid CB receptors, CB and CB receptors, at the have been used as natural remedies and also as fra- 1 2 peripheral and central sites have been proposed to medi- grances. This compound is also known to be anti-micro- ate the CB-induced antinociceptive effects [13-17]. CB bial [3], anti-oxidant [3,4], and anti-carcinogenic [5] and 2 receptors are not found in the central nervous system to possess skin penetration-enhancing properties [6]. (CNS), but are predominantly expressed in immune cells, Moreover, BCP is also a major component in the essen- their roles including the modulation of cytokine release tial oil of Cannabis sativa L [7]. BCP showed marked and immune cell migration [18,19]. CB receptor selec- anti-inflammatory activity against carrageenan- and pro- 2 tive agonists produced peripheral antinociception [15, *Corresponding author. 20,21], but do not cause the effects of CNS [15,22], sug- Copyright © 2012 SciRes. PP 398 Local Peripheral Effects of β-Caryophyllene through CB2 Receptors in Neuropathic Pain in Mice gesting that selective activation of CB2 receptors may tion of motor disorders or change in weight. Testing achieve the goal of peripheral pain relief without CNS procedures were conducted on day 7 after PSNL, except effects. Therefore, in our study we used local injections for the time-course experiment of PSNL-induced allody- to the injured paw in order to exclude the role of central nia. effects, and validate the role of peripheral CB receptors in neuropathic pain. Peripheral nerve damage can result 2.2. Mechanical Threshold in long-lasting anomalous pain conditions referred to as Behavioral testing was conducted from 10:00 to 16:00 in neuropathic pain. These abnormal pain states are often a quiet room. Each animal received drugs only once and manifested by an increased sensitivity to nociceptive was used in only one experiment. The mice were stimuli, termed hyperalgesia, as well as the perception of weighed and placed individually in a Plexiglas chamber typical innocuous stimuli being painful, a state referred (11.0 × 17.0 × 14.0 cm, wire mesh floor) and allowed to to as allodynia [23]. CB2 receptor selective agonists have acclimatize for at least 1 hour. The threshold for nocicep- been also known to produce antinociception without tive responsiveness to mechanical stimuli applied to the overt behavioral effects in neuropathic pain [20,22,24, hindpaw was assessed using an electronic version of the 25]. The aims of this work was 1) to investigate whether von Frey test (dynamic plantar anesthesiometer, model i.pl. injection of BCP would produce antinociception in 37400; Ugo Basile, Milan, Italy). The servo-controlled PSNL-induced mechanical allodynia model in mice; and mechanical stimulus (a pointed metallic filament) was 2) to determine a possible role of peripheral CB recap- applied to the plantar surface, which exerted a progres- tors in BCP-induced anti-allodynic effects. sively increasing punctate pressure, reaching up to 3.0 g within 5.0 s. The pressure evoking a clear voluntary hind- 2. Materials and Methods paw withdrawal response (usually close to 3.0 g) was 2.1. Animals and Neuropathic Surgery recorded automatically and taken as the mechanical no- ciceptive thereshold index. Male mice of ddY strain weighing 22 - 24 g were pur- chased from Kyudo Industries, Kumamoto, Japan. They 2.3. Drugs were housed in cages of 15 - 20 animals matched for weight and placed in a colony room. Animals were al- β-Caryophyllene(trans-(1R,9S)-8-Methylene-4,11,11-tri- lowed free access to standard food (Clea Japan, Inc., methylbicyclo [7.2.0] undec-4-ene; BCP) (Sigma, St. Osaka, Japan) and tap water in an air-conditioned room Louis, MO, USA) diluted in jojoba wax (Simmondsia under a constant 12:12 h light/dark cycle (light on 08:00 chinensis) (KSA International, Co. Ltd., Kanagawa, Ja- h) at a room temperature of 22˚C - 24˚C and 50% - 60% pan), was injected to the plantar surface of the hindpaw relative humidity. All experiments followed the Guide- in mice. N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlo- lines on Ethical Standards for Investigation of Experi- rophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) mental Pain in Animals [26]. Additionally, the study was and 6-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-in- approved by the Committee of Animal Experiments in dol-3-yl] (4-methoxyphenyl) methanone (AM630) (Toc- Daiichi College of Pharmaceutical Sciences. ris Cookson, Bristol, UK), dissolved in physiological Partial ligation of the sciatic nerve of mice was per- saline was administered i.pl. or subcutaneous (s.c.) 30 formed under pentobarbital anesthesia (50 mg/kg, i.p.) min before BCP. I.pl. and s.c. injections were given in a following the methods Malmberg and Basbaum [27]. volume of 20 μL/site and 0.1 mL/10 g of body weight, Briefly, the common sciatic nerve of the right hand leg of respectively. mice was exposed at high thigh level through a small incision and dorsal 13 to 12 of the nerve thickness 2.4. Analyses of Data was tightly ligated with a silk suture. The wound was All data are expressed as means ± SEM. Statistical dif- closed with a single muscle suture, and antibiotic powder ferences between groups were assessed with a two-way was dusted over the wound area following surgery. For ANOVA followed by Bonferroni’s test. The 5% (P < sham surgery, the sciatic nerve was exposed as described 0.05) level of statistical significance was set in all ex- above, but no contact was made with the nerve. To periments. minimize differences in technique, all operations were done by the same person. Immediately following surgery, 3. Results the animals were kept in a soft bag cage with some food 3.1. The Effects of BCP on Mechanical Allodynia inside so that they could feed themselves without having difficulty in standing. The wound healed within 1 to 2 The responsiveness to mechanical stimuli was deter- days, and the mice behaved normally. The behavior of mined on days 1 - 35 after PSNL. Compared with the the mice was monitored carefully for any visual indica- sham-operated mice, PSNL resulted in mechanical allo- Copyright © 2012 SciRes. PP Local Peripheral Effects of β-Caryophyllene through CB2 Receptors in Neuropathic Pain in Mice 399 dynia demonstrated by significantly lower threshold to BCP, whereas AM251 (12.0 μg/paw) gave no effect von Frey filaments from day 7 to day 28 post-PSNL (Figure 4).
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